Click-chemistry compatible structures, click-chemistry functionalized structures, and materials and methods for making the same

ABSTRACT

According to several embodiments, a composition of matter includes: a three-dimensional structure comprising photo polymerized molecules. At least some of the photo polymerized molecules further comprise one or more protected click-chemistry compatible functional groups; and at least portions of one or more surfaces of the three-dimensional structure are functionalized with one or more of the protected click-chemistry compatible functional groups.

The United States Government has rights in this invention pursuant toContract No. DE-AC52-07NA27344 between the United States Department ofEnergy and Lawrence Livermore National Security, LLC for the operationof Lawrence Livermore National Laboratory.

FIELD OF THE INVENTION

The presently disclosed inventive concepts relate to additivemanufacturing techniques and compositions, and particularly tocompositions suitable for use in additive manufacturing to fabricatestructures that are compatible with click-chemistry, as well asstructures that have been functionalized via click chemistry.

BACKGROUND

In the field of additive manufacturing, many techniques exist to createstructures with precise control over the features of the structure.Recently, techniques based on photo-activation of precursor components,such a projection microstereolithography (PμSL) have receivedsignificant attention. To date, such techniques have been demonstratedand proven effective for making structures that consist of crosslinkedpolymers in nearly any shape or configuration.

However, the structures created via these photo-activation-basedadditive manufacturing techniques consist of the crosslinked polymers,i.e. inert plastic. While creating such structures consisting ofcrosslinked polymers is itself advantageous from a manufacturingstandpoint, this does not provide any chemically- and/orbiologically-relevant applicability to the resulting structures.

Accordingly, it would be highly beneficial to provide techniques andsuitable materials that are capable of generating structures with theprecise control afforded by photo-activation-based additivemanufacturing, while also enabling the resulting structure to havefurther functionality that is chemically- and/or biologically relevantto a variety of industrial, pharmaceutical, etc. applications.

SUMMARY

In one embodiment, a composition of matter includes: a three-dimensionalstructure comprising photo polymerized molecules. At least some of thephoto polymerized molecules further comprise one or more protectedclick-chemistry compatible functional groups; and at least portions ofone or more surfaces of the three-dimensional structure arefunctionalized with one or more of the protected click-chemistrycompatible functional groups.

Other aspects and embodiments of the present invention will becomeapparent from the following detailed description, which, when taken inconjunction with the drawings, illustrate by way of example theprinciples of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

For a fuller understanding of the nature and advantages of the presentinvention, reference should be made to the following detaileddescription read in conjunction with the accompanying drawings.

FIG. 1 is a simplified schematic of a projection microstereolithography(PμSL) apparatus, according to one embodiment.

FIG. 2 is a simplified reaction scheme for forming a single-componentresin for additively manufacturing click-chemistry compatiblestructures, according to another embodiment.

FIG. 3 is a simplified reaction scheme for forming a dual-componentresin for additively manufacturing click-chemistry compatiblestructures, according to another embodiment.

FIG. 4 is a simplified reaction scheme for forming a resin foradditively manufacturing click-chemistry compatible structures,according to another embodiment.

FIG. 5 is a flowchart of a method for forming a single-component resinfor additively manufacturing click-chemistry compatible structures,according to various embodiments.

FIG. 6 is a flowchart of a method for forming a dual-component resin foradditively manufacturing click-chemistry compatible structures,according to various embodiments.

FIG. 7A depicts simplified structures comprising a terminal alkynefunctionalized with a protecting group, according to variousembodiments.

FIG. 7B depicts simplified structures comprising a photo polymerizablecompound featuring a terminal alkyne functionalized with a protectinggroup (left) and a reaction scheme for deprotecting the terminal alkyneto form a photo polymerizable, click-chemistry compatible molecule,according to one embodiment.

FIGS. 8A and 8B depict embodiments of a three-dimensional structureformed by additive manufacturing as disclosed herein. The structure hassurfaces which are functionalized to be click-chemistry compatible, andin FIG. 8B the structure is further functionalized via click chemistryto incorporate a fluorescing group onto the surfaces of the structure.

FIG. 9 depicts a simplified reaction scheme for forming the structuresas shown in FIGS. 8A and 8B, in one embodiment.

FIG. 10 is a flowchart of a method for additively manufacturingclick-chemistry compatible structures as disclosed herein, according toone approach.

FIG. 11 is a flowchart of a method for functionalizing click-chemistrycompatible structures as disclosed herein, according to one embodiment.

FIG. 12 depicts a simplified reaction scheme for copper-catalyzed alkyneazide cycloaddition (CuAAC) click chemistry, according to oneembodiment.

FIG. 13 depicts a simplified reaction scheme for photo-activation-basedadditive manufacturing using precursor materials comprising acrylatefunctional groups, in one approach.

FIG. 14 depicts a simplified reaction scheme for photo-activation-basedadditive manufacturing using precursor materials comprising epoxidefunctional groups, in one approach.

FIG. 15 depicts a simplified reaction scheme for photo-activation-basedadditive manufacturing using precursor materials comprising thiol-enefunctional groups, in one approach.

FIG. 16 depicts exemplary simplified structures suitable for use asprecursor materials in photo-activation-based additive manufacturing,according to various illustrative embodiments.

DETAILED DESCRIPTION

The following description is made for the purpose of illustrating thegeneral principles of the present invention and is not meant to limitthe inventive concepts claimed herein. Further, particular featuresdescribed herein can be used in combination with other describedfeatures in each of the various possible combinations and permutations.

Unless otherwise specifically defined herein, all terms are to be giventheir broadest possible interpretation including meanings implied fromthe specification as well as meanings understood by those skilled in theart and/or as defined in dictionaries, treatises, etc.

As also used herein, the term “about” when combined with a value refersto plus and minus 10% of the reference value. For example, a length ofabout 1 μm refers to a length of 1 μm±0.1 μm.

It must also be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless otherwise specified.

As utilized herein, it should be understood that “click-chemistrycompatible” structures, functional groups, monomers, oligomers, etc.,refer to compounds, materials, etc. that are structurally characterizedby including one or more chemical moieties suitable for participation ina click-chemistry reaction. In embodiments where copper-catalyzedazide-alkyne cycloaddition (CuAAC) is the click-chemistry employed forfunctionalizing materials as disclosed herein, the “click-chemistrycompatible” compounds include a terminal alkyne and/or terminal azidefunctional group.

The exemplary and preferred click-chemistry reaction described herein isCuAAC, although skilled artisans will appreciate that otherclick-chemistry compatible reactions that would be appreciated asequivalent to CuAAC upon reading these descriptions may be employedwithout departing from the scope of the inventive concepts describedherein. For instance, in various embodiments click-chemistry compatiblereactions may include CuAAC, strain-promoted azide-alkyne cycloaddition(SPAAC), strain-promoted alkyne-nitrone cycloaddition (SPANC), strainedalkene reactions such as alkene-azide cycloaddition, etc.Click-chemistry compatible reactions may also be considered to includealkene-tetrazine inverse-demand Diers-Alder reactions, alkene-tetrazolephotoclick reactions, Michael additions of thiols, nucleophilicsubstitution of thiols with amines, and certain Diels-Alder reactions,etc. such as disclosed by Becer, et al. “Click chemistry beyondmetal-catalyzed cycloaddition.” Angew. Chem. Int. Ed. 2009, 48: p.4900-4908, and equivalents thereof as would be understood by a personhaving ordinary skill in the art upon reading the present disclosures.Accordingly, click-chemistry compatible groups, compounds, etc. shouldbe understood to include one or more suitable chemical moietiesconveying capability to participate in any combination of the foregoingexemplary click chemistries, in various embodiments.

As described herein, “photo polymerizable” compounds, groups, etc. arestructurally characterized by including one or more chemical moietiessuitable for causing polymerization of the such compounds, groups, etc.under suitable environmental conditions including exposure of the photopolymerizable compound and/or an intermediate reagent (such as aphotoactivator, photoinitiator, etc. as described herein and would beappreciated by skilled artisans upon reading the present disclosure).Preferred embodiments of such photo polymerizable compounds according tothe presently described inventive concepts, and particularly thoseembodiments that employ projection microstereolithography, include:acrylates, epoxides, and thiol-enes. Of course, skilled artisans willappreciate that other photo polymerizable groups, compounds, etc. thatwould be appreciated as equivalent to acrylates, epoxides, andthiol-enes may be employed without departing from the scope of thepresent disclosures.

The following description discloses several preferred embodiments ofclick-chemistry compatible and/or functionalized structures, as well asrelated compositions, systems and methods of making the same.

In one general embodiment, a composition of matter includes: athree-dimensional structure comprising photo polymerized molecules. Atleast some of the photo polymerized molecules further comprise one ormore protected click-chemistry compatible functional groups; and atleast portions of one or more surfaces of the three-dimensionalstructure are functionalized with one or more of the protectedclick-chemistry compatible functional groups.

In another general embodiment, an additive manufacturing resin suitablefor fabricating a click-chemistry compatible composition of matterincludes: a photo polymerizable compound; and a click-chemistrycompatible compound.

In yet another general embodiment, a method of forming an additivemanufacturing resin suitable for fabricating a click-chemistrycompatible composition of matter includes: reacting a compoundcomprising a terminal alkyne group or a terminal azide group with aprotecting reagent to form a protected reactive diluent precursor, theprecursor comprising the terminal alkyne group or the terminal azidegroup; reacting the precursor with a compound comprising a photopolymerizable group to form a protected reactive diluent; and mixing theprotected reactive diluent with a photo polymerizable compound to formthe additive manufacturing resin.

Turning now to FIG. 1, a simplified schematic of an exemplary apparatus100 for performing photocatalytic additive manufacturing, such as PμSL,is shown according to one embodiment. The apparatus 100 generallyincludes a synthesis portion 110 comprising a reservoir 112 and a stage114. The reservoir 112 may comprise any suitable materials and/orconfiguration that would be understood by a person having ordinary skillin the art, and should be characterized by dimensions suitable to allowthe stage 114 to be contained within an inner volume of the reservoir112. The stage 114 similarly may comprise any suitable materials and/orconfiguration, and preferably includes a flat lower portion upon which aproduct may be formed via additive manufacturing. In particularlypreferred approaches, the stage 114 is configured to change positionwithin the reservoir 112 along at least a z-axis, as shown in FIG. 1.More preferably, the stage 114 may also be configured to change positionwithin the reservoir 112 along an x and/or y axis. Alternatively,another mechanism may move the reservoir 112 along x, y and/or z axeswhile the stage 114 remains stationary.

The apparatus 100 further comprises an optics portion, which includes alight source 102, a digital mask 104, a mirror 106 (optional) and aprojection lens 108. Each component of the optics portion is arranged toform a beam path from the light source 102 to the reservoir 112.Preferably, the light source is monochromatic, and emits a wavelength oflight tuned to the photoinitiator band of the precursor 116, e.g. aphotopolymer resin.

The digital mask 104 may include any suitable mask that would beunderstood by a person having ordinary skill in the art upon reading thepresent descriptions, and may in some approaches comprise an array ofmicro mirrors configured to selectively reflect light (dashed lines)from the light source 102 toward the mirror 106 and/or projection lens108, or away from the mirror 106 and/or projection lens 108. In otherembodiments, the digital mask 104 may include a liquid crystal onsilicon (LCoS) device.

The selectivity of the reflection may be defined based on acomputer-generated digital pattern corresponding to a layer 120 _(a) . .. 120 _(n) of a structure to be created using the apparatus 100.

Accordingly, the apparatus 100 may be communicatively coupled to acomputer or other suitable device and receive therefrom instructionsregarding a particular pattern or series of patterns to utilize forselectively directing light from the light source 102 to the reservoir112 as part of an additive manufacturing process.

Accordingly, in operation, apparatus 100 facilitates the manufacture ofcustom-designed structures with extreme precision, e.g. characterized bya feature size on the scale of 10⁻²-10³ microns, in some embodiments. Invarious embodiments, features may be characterized by a feature size onthe scale of 10 nm to several hundred (e.g. 300-500) nm, a feature sizeon the scale of several hundred nm to several hundred microns, a featuresize on the scale of several hundred nm to several mm, etc., e.g.including embodiments in which the feature size may be in a rangedetermined based on the type of formation process employed to fabricatethe structures and as would be understood by a person having ordinaryskill in the art upon reviewing the present disclosures.

As described herein, features should be understood to include anysuitable component, portion, etc. of a three-dimensional structure, aswould be understood by a person having ordinary skill in the art uponreading the present descriptions. For instance, in various embodiments,features may include protrusions, depressions, voids, lattices,channels, pockets, pillars, points, overhangs, cantilevers, positivefeatures at various angles, etc. as skilled artisans will appreciateupon reviewing the instant disclosure. Generally, and due to the highlevel of precision afforded by PμSL, any of the foregoing features maybe formed at nearly any angle.

To accomplish this result, a precursor 116 is placed in the reservoir112, and the stage 114 is positioned within the reservoir 112 in such amanner that the lower portion of the stage 114 is submerged in theprecursor 116 to a predetermined depth corresponding to a thickness of alayer 120 _(a) . . . 120 _(n) of the structure to be fabricated.

The precursor 116 may include any suitable material, and preferablyincludes one or more photo-curable resins. In various approaches, theprecursor 116 is preferably a liquid, optionally a viscous liquid, andmay include one or more photopolymers, e.g. a combination ofphotoinitiator and oligomers, such as hexane diol diacrylate (HDDA),polyethylene glycol diacrylate (PEGDA), pentaerythritol triacrylate(PETA) ethylene glycol dimethacrylate (EGDMA), epoxides, silicones,thiol-enes, and/or other suitable photopolymers for forming a solidstructure via PμSL that would be understood by a person having ordinaryskill in the art upon reading the present disclosure. Precursor 116 maybe in the form of a solution, a mixture, etc. and may optionally includephotoactive reduction inhibitor(s), photo reductant(s) and/orphotoabsorber(s). In preferred approaches at least two of the foregoingoptional compositions are included, and in particularly preferredembodiments at least the photoabsorber, which advantageously enhancesfeature resolution by decreasing the resin's sensitivity to light, ispresent.

The photo-curable resin(s) are characterized by forming solids, e.g. viacrosslinking polymers in the precursor 116, in response to exposure ofthe precursor 116 to light (dashed lines) from the light source 102.Accordingly, it is possible to define a precise three-dimensionalstructure via a series of patterns to be applied via the digital mask104 and selectively expose a predetermined thickness/depth of theprecursor 116 to the light from light source 102 and form,layer-by-layer, regions 118 of solid material from the precursor 116.

As shown in FIG. 1, the structure formed using the apparatus 100 thusincludes a plurality of layers 120 _(a) . . . 120 _(n) each formedaccording to a single exposure from the light source 102 and accordingto a pattern defined by the digital mask 104. In between formation ofeach layer 120 _(a) . . . 120 _(n), the stage 114 is moved within thereservoir (and/or the reservoir 112 is moved relative to the stage 114)to facilitate formation of a subsequent layer on the previously formedlayer. According to FIG. 1, the structure is characterized by aplurality of layers 120 _(a) . . . 120 _((n-1)), and the apparatus 100is in the process of forming a final layer 120 _(n) on layer 120_((n-1)) by exposing precursor 116 above layer 120 _((n-1)) to lightfrom the light source 102. In response to the exposure, in the regions118 to which the precursor 116 is exposed the photopolymer initiates acrosslinking process and solidifies in the corresponding regions 118(shown by dashed line rectangles in layer 120 _(n) of FIG. 1).

In the foregoing manner, extremely precise control over structural andpositional arrangement of the resulting component is enabled. While thestructure shown in FIG. 1 has a substantially rectangular, simpleprofile and arrangement of component portions, more complex structuressuch as shown in FIGS. 2A-2B are equally feasible, in variousapproaches.

The foregoing descriptions of an apparatus 100 as shown in FIG. 1 and acorresponding fabrication process should be understood as exemplary,nonlimiting illustrations of a suitable apparatus 100 and fabricationprocess suitable for use in the context of the presently disclosedinventive concepts. It will be appreciated by a person having ordinaryskill in the art upon reading the present descriptions that otherapparatuses and/or fabrication processes, particularly additivemanufacturing and three-dimensional printing processes such asstereolithography, deposition modeling, continuous liquid interfaceproduction and binder printing may be employed without departing fromthe scope of the instant descriptions.

However, in preferred approaches an apparatus 100 as shown in FIG. 1 andPμSL manufacturing process are implemented to form structures havingclick-chemistry compatible groups, e.g. terminal azides and/or alkynes,functionalized on surfaces thereof. The surfaces may include outersurfaces, as well as surfaces of pores that may optionally be presentthroughout portions or an entirety of the structure.

Accordingly, it should be appreciated that the presently disclosedinventive concepts represent a novel technique for generatingselectively functionalized structures via additive manufacturing and/orthree-dimensional printing processes. The novel techniques result innovel structures with click-chemistry compatible functional groups onsurfaces thereof, which advantageously allows for a variety of furthersurface functionalization using a variety of organic additives alsocharacterized by having functional group(s) compatible withclick-chemistry such as copper-catalyzed azide alkyne cycloaddition(CuAAC) reaction schemes. Other suitable chemistries may be employedwithout departing from the scope of the present disclosures, asdescribed in further detail herein, such as the exemplary chemistriesset forth herein.

As discussed above with reference to FIG. 1 photo-activated additivemanufacturing techniques such as projection microstereolithography mayadvantageously be leveraged to form chemically- and/orbiologically-relevant structures that are compatible withclick-chemistry and/or functionalized via click-chemistry. Suchfunctionalization preferably provides additional functional capabilitiesto the structures, via surface modification configured to add a varietyof organic additives advantageous or suitable to a particularapplication, such as the exemplary applications and uses described infurther detail below.

In order to form structures that are click-chemistry compatible andconvey the advantageous additional functionality discussed herein, it isnecessary to utilize precursor materials that are unique from theconventional precursor materials employed to-date for photo-activatedadditive manufacturing. The presently disclosed inventive conceptstherefore include embodiments comprising unique synthetic pathways forgenerating precursor materials that are suitable for photo-activatedadditive manufacturing of structures that are click-chemistrycompatible.

For instance, in one approach, a simplified reaction scheme 200 forforming a single-component resin is shown in FIG. 2. Thesingle-component resin is suitable for use in for additivelymanufacturing click-chemistry compatible structures. As discussedherein, the term “single-component” refers to the existence of a singlecomponent that participates in the photo-activated additivemanufacturing reaction (e.g. as shown in FIGS. 13-15, and described infurther detail below). Those having ordinary skill in the art willappreciate, upon reading the instant disclosures, that the resinaccording to various embodiments may include other materials, such asphotoactivators, photoabsorbers, photoinitators, etc. In furtherembodiments, single-component resins may include multiple differenttypes of functional group(s) suitable for photo-activated additivemanufacturing, such as acrylates (shown in FIG. 2), epoxides,thiol-enes, and/or other functional groups associated with the variousclick-compatible chemistries disclosed herein.

The reaction scheme 200 features formation of oligomers comprisingfunctional groups structurally appropriate for forming crosslinks withother similar oligomers to enable photo-activated additive manufacturing(interchangeably referred to herein as a crosslinking group or aphoto-polymerizable group), as well as functional groups structurallyappropriate for participating in click-chemistry reactions afterformation of a structure from the oligomer precursors (e.g. viaphoto-activated additive manufacturing). In particular, according toFIG. 2 the oligomers include acrylate groups to convey capability forcrosslinking with other oligomers, but in other embodiments, epoxideand/or thiol-ene groups may additionally and/or alternatively beincluded in the oligomer. The oligomers also include terminal alkynegroups to convey click-chemistry compatibility to the resin andresulting structures produced by additive manufacturing.

In still further embodiments different oligomers having differentphoto-activated additive manufacturing compatible functional groups maybe included in a single-component resin. Oligomers having acrylategroups, second oligomers having epoxide groups, and third oligomershaving thiol-ene groups may be included in any combination, forinstance. Of course, all possible combinations of oligomers having anycombination of the above functional groups may also be present, invarious embodiments.

The reaction scheme 200 as shown in FIG. 2 includes reacting a compound202 comprising a terminal alkyne, e.g. (2-hydroxyethyl)acetylene, withan azole, e.g. carbonyldiimidazole (CDI) and an amine, e.g.diethanolamine. This reaction results in formation of a precursor 204 tothe single-component resin 206.

As shown in FIG. 2, the precursor 204 includes two hydroxyl groupssuitable for participation in a subsequent substitution reaction to formthe single-component resin 206. In particular, each hydroxyl mayparticipate in a substitution reaction with a compound comprising aphoto polymerizable group, e.g. an R-substituted acryloyl halidereagent, to impart acrylate groups onto the precursor at the hydroxylsite. The substitution reaction may be carried out in the presence of abase such as diisopropylethylamine (DIPEA) or other equivalent reagents,in various embodiments.

The resulting single-component resin 206 according to the embodimentshown in FIG. 2 is an oligomer including acrylate groups suitable forcrosslinking to other oligomer molecules in the single-component resin206 as well as a terminal alkyne group suitable for participating inclick-chemistry reactions.

Exposing resin 206, which preferably includes a suitable photoinitiator,to a particular wavelength of light, e.g. light having a wavelength inthe UV range, results in crosslinking of the oligomers thereof in theexposed regions of the resin 206. In one approach, where acrylate groupsare present in the oligomers of the resin 206, crosslinking may proceedaccording to a reaction scheme 1300 as depicted in FIG. 13. Acrylategroups may interact with radicals generated by a photoinitiator,resulting in crosslinking of the oligomers of the resin 206.

In various embodiments where the single-component resin includes otherfunctional groups suitable for crosslinking the oligomers, exposing theresin 206 to the particular wavelength of light may cause crosslinkingvia other reaction schemes, e.g. reaction schemes 1400 and/or 1500 asshown in FIGS. 14 and 15, respectively for epoxide groups and thiol-enegroups. Notably, the epoxide-based crosslinking reaction scheme 1400does not rely on interaction with a radical (as is the case for theacrylate groups and thiol-ene groups) but rather is driven by cationsgenerated by the photoinitiator. Additionally, related vinyl ether andN-vinyl carbazoles containing oligomers are also crosslinked in thepresence of cations and can additionally and/or alternatively beemployed as a photo polymerizable group or compound, in certainembodiments.

Accordingly, in one embodiment a method 500 of forming an additivemanufacturing resin, such as a single-component resin 206, is shown inFIG. 5. The particular method 500 may vary with respect to the chemistryemployed, according to different embodiments and depending on theidentity of the functional groups to be included for the purpose ofadditive manufacturing (e.g. crosslinking) and the functional groups tobe included for the purpose of conveying click-chemistry compatibilityon the resulting resin.

According to the embodiment depicted in FIG. 5, method 500 includesoperation 502, in which a compound comprising a terminal alkyne or aterminal azide (e.g. 202) is reacted to form a photo polymerizableoligomer precursor (e.g. 204) including the terminal alkyne or azidegroup.

With continuing reference to FIG. 5, method 500 also includes operation504, where the photo polymerizable oligomer precursor is reacted with acompound comprising a photo polymerizable group (e.g. acrylate, epoxide,and/or thiol-ene groups) to form an additive manufacturing resin (e.g.206).

As mentioned with respect to FIG. 2, in various embodiments the compoundcomprising the photo polymerizable group may be an R-substitutedacryloyl halide reagent, e.g. acryloyl chloride or 2-methyl-2-propenoylchloride. Of course, other suitable photo polymerizable groups such asepoxides and thiol-enes, vinyl ethers and N-vinyl carbazoles containingoligomers, as well as compounds containing the same may be used inalternative embodiments.

For instance, in one embodiment the photo polymerizable compound may beor include a polyethylene-glycol backbone functionalized with at leastone photo polymerizable moiety selected from a group consisting of:acrylates, epoxides, and thiol-enes. Additionally and/or alternatively,in some embodiments the photo polymerizable compound comprises anorganic backbone, e.g. a hexanediol-based backbone, a polyethyleneglycol-based backbone, a vinyl-based backbone, etc. functionalized withat least one photo polymerizable moiety selected from a group consistingof: acrylates, epoxides, thiol-enes, vinyl ethers and N-vinyl carbazolescontaining oligomers. As such, exemplary photo polymerizable compoundsin various embodiments may include PEGDA, pentaerythritol triacrylate(PETA) EGDMA, HDDA, etc.

In more embodiments, the photo-polymerizable compounds described hereinmay include any moiety, structure, etc. as set forth in FIG. 16.

In more embodiments, reacting the compound comprising the terminalalkyne group or the terminal azide group to form the precursor may beperformed in the presence of an azole (e.g. CDI) and an amine (e.g.diethanolamine).

In still more embodiments, reacting the precursor with the compoundcomprising the photo polymerizable group is performed in the presence ofa base, e.g. DIPEA.

Of course, the foregoing exemplary method 500 contemplates formingsingle-component additive manufacturing resins where the photopolymerizable group leveraged for additive manufacturing is one or moreacrylate functional groups, and a terminal alkyne providesclick-chemistry compatibility. In other embodiments, the method 500 mayemploy different chemistry than shown in the reaction scheme 200 inorder to accommodate azide-based click-chemistry compatibility, and/orepoxide or thiol-ene-based crosslinking and additive manufacturing.

In another approach, a simplified reaction scheme 300 for forming adual-component resin for additively manufacturing click-chemistrycompatible structures is shown in FIG. 3. As will be explained infurther detail below, dual-component resins are advantageouslycharacterized by including a reactive diluent monomer, which may havethe click-chemistry compatible functional group thereof optionally andpreferably protected to as to control the ability of the resulting resinand structures formed therewith to participate in click-chemistry orother reactions. In particularly preferred approaches, the protection ofthe click-chemistry compatible group prevents this group from reactingwith other components of the resin during the additive manufacturingprocess, e.g. from reacting with radicals or cations generated by aphotoinitiator.

To be clear, reactive diluent monomers and/or oligomers as describedherein need not be functionalized with protecting groups to be effectivein click-chemistry or other synthesis schemes disclosed herein. However,preferred embodiments of click-chemistry compatible structures include aprotective group functionalized to the functional group thatparticipates in the cycloaddition or other synthesis reaction.Particularly in the case of alkynes, protection advantageously improvesthe degree to which a formed product is functionalized on surfacesthereof by preventing the alkynes from polymerizing during thefabrication process.

As discussed herein, the term “dual-component” refers to the existenceof two components that participate in the photo-activated additivemanufacturing reaction (e.g. as shown in FIGS. 13-15, and described infurther detail below). In further embodiments, dual-component resins mayinclude multiple different types of functional group(s) suitable forphoto-activated additive manufacturing, such as acrylates (shown in FIG.3), epoxides, thiol-enes, and/or any other suitable functional groupsassociated with different click-chemistry schemes of the various typesdisclosed herein.

Those having ordinary skill in the art will appreciate, upon reading theinstant disclosures, that the resin according to various embodiments mayinclude other materials, such as photoactivators, photoabsorbers,photoinitators, solvents (e.g. dimethylformamide, dimethylacetamide,tetrahydrofuran (THF), toluene, acetone, etc.), viscosity modifyingagents (such as stabilizers, binders, surfactants, etc.), and/orpore-forming compounds (e.g. silica nanoparticles, uncrosslinkedpolystyrene beads, suitable salts such as sodium chloride, etc.), and/orother suitable materials that would be understood by a skilled artisanupon reading the instant descriptions.

The reaction scheme 300 features formation of reactive diluentscomprising functional groups structurally appropriate for formingcrosslinks with other similar reactive diluents and/or crosslinkercomponents (e.g. PEGDA, EGDMA, PETA, HDDA, etc.) to enablephoto-activated additive manufacturing. The reactive diluents alsoinclude functional groups structurally appropriate for participating inclick-chemistry reactions after formation of a structure from thereactive diluent and crosslinker components via photo-activated additivemanufacturing.

In particular, according to FIG. 3 the reactive diluents includeacrylate groups to convey capability for crosslinking with otheroligomers, but in other embodiments epoxide and/or thiol-ene groups mayadditionally and/or alternatively be included in the reactive diluent.The reactive diluent also includes a terminal alkyne group for thepurpose of providing click-chemistry compatibility to the dual-componentresin 306. Preferably, and again as shown in FIG. 3, the reactivediluent features a protecting group (e.g. trimethylsilane, TMS)functionalized to the terminal alkyne in order to prevent the terminalalkyne participating in radical interactions or other reactionsoccurring during the crosslinking additive manufacturing process.Protecting groups and techniques for deprotecting click-chemistrycompatible compounds/groups as described herein will be discussed infurther detail below regarding FIGS. 7A-7B.

In still further embodiments different reactive diluents havingdifferent photo-activated additive manufacturing compatible functionalgroups may be included in a dual-component resin. Reactive diluentshaving acrylate groups, second reactive diluents having epoxide groups,and third reactive diluents having thiol-ene groups may be included inany combination, for instance. Of course, all possible combinations ofreactive diluents having any combination of the above functional groupsmay also be present, in various embodiments.

The reaction scheme 300 as shown in FIG. 3 includes reacting a compound302 comprising a terminal alkyne (e.g. (2-hydroxyethyl)acetylene) with aprotecting reagent, i.e. a compound such as TMS, e.g. trimethylsilanechloride (TMSCl), and an organolithium reagent (e.g. n-butyllithium(nBuLi)). The resulting compound can then be treated with an acidsolution, preferably a strong acid such as hydrochloric acid.

The resulting protected reactive diluent precursor 304 features aterminal alkyne functionalized with a protecting group, TMS as shown inFIG. 3. The protected reactive diluent precursor 304 also includes ahydroxyl moiety suitable for participating in a substitution reactionwith a compound featuring a functional group suitable forphoto-activated additive manufacturing, e.g. a crosslinking group suchas an acrylate, epoxide, and/or thiol-ene functional group. As shown inFIG. 3, the compound utilized for this purpose is an R-substitutedacryloyl halide. The R— group may be a functional group selected fromhydrogen, methyl, etc. in various embodiments.

Reacting the protected reactive diluent precursor 304 with the compoundhaving the crosslinking group (also referred to as a photo-polymerizablegroup) in the presence of DIPEA to form a protected reactive diluent,one of the two components of the dual component resin 306. Where thecompound having the crosslinking group(s) is a 2-acryloyl halide orR-substituted derivative thereof, the halide acts as a leaving group andthe compound binds to the hydroxyl terminus of the protected reactivediluent precursor 304, according to the reaction scheme 300 shown inFIG. 3.

After forming the protected reactive diluent according to reactionscheme 300 as shown in FIG. 3, the protected reactive diluent may becombined with a crosslinker component, e.g. PEGDA, EGDMA, PETA, HDDA,etc. as would be understood by a person having ordinary skill in the artupon reading the present descriptions, in order to complete thedual-component additive manufacturing resin 306.

Of course, in various approaches other materials may be included in suchdual-component additive manufacturing resins, e.g. photoinitiators,photoabsorbers, etc. as disclosed herein and as would be appreciated bya person having ordinary skill in the art upon reading the presentdisclosures.

The resulting dual-component resin 306 according to the embodiment shownin FIG. 3 includes a protected reactive diluent monomer includingacrylate, epoxide, and/or thiol-ene groups suitable for crosslinking toother protected reactive diluent monomers in the dual-component resin306 as well as a terminal alkyne group suitable for participating inclick-chemistry reactions. In various embodiments the terminal alkynemay be replaced with a terminal azide, as shown in FIG. 4. Thedual-component resin also includes a crosslinker such as PEGDA, EGDMA,PETA, HDDA, etc. having functional groups such as acrylates, epoxides,and/or thiol-enes for participating in polymerization, e.g. viacrosslinking, during photo-activated additive manufacturing. Thepolymerization/crosslinking reaction in the case of a dual-componentresin 306 also results in the incorporation of the dilutive reactantwith the click-chemistry compatible functional group(s) into the polymerand thus the structures produced via additive manufacturing. Suitableprocesses for forming structures functionalized with click-chemistrycompatible functional groups will be described in further detail belowregarding FIG. 10, and techniques for further functionalizing suchstructures will be described in further detail below with respect toFIG. 11, according to several exemplary embodiments.

Exposing the resin 306, which preferably includes a suitablephotoinitiator, to a particular wavelength of light, e.g. light having awavelength in the UV range, results in crosslinking of the oligomersthereof in the exposed regions of the resin 306. In one approach, whereacrylate groups are present in the oligomers of the resin 306,crosslinking may proceed according to a reaction scheme 1300 as depictedin FIG. 13. Acrylate groups may interact with radicals generated by thephotoinitiator, resulting in crosslinking of the oligomers of the resin306.

In various embodiments where the dual-component resin includes otherfunctional groups suitable for crosslinking the oligomers, exposing theresin 306 to the particular wavelength of light may cause crosslinkingvia other reaction schemes, e.g. reaction schemes 1400 and/or 1500 asshown in FIGS. 14 and 15, respectively for epoxide groups and thiol-enegroups. Notably, the epoxide-based crosslinking reaction scheme 1400does not rely on interaction with a radical (as is the case for theacrylate groups and thiol-ene groups) but rather is driven by cationsgenerated by the photoinitiator in response to exposure to light of aparticular wavelength.

Accordingly, in one embodiment a method 600 of forming an additivemanufacturing resin, such as a dual-component resin 306, is shown inFIG. 6. The particular method 600 may vary with respect to the chemistryemployed, according to different embodiments and depending on theidentity of the functional groups to be included for the purpose ofadditive manufacturing (e.g. crosslinking) and the functional groups tobe included for the purpose of conveying click-chemistry compatibilityon the resulting resin.

As shown in FIG. 6, method 600 includes operation 602, in which acompound comprising a click-chemistry compatible functional group suchas a terminal alkyne or a terminal azide group (e.g. 302) is reactedwith a protecting reagent to form a protected reactive diluent precursor(e.g. 304) that includes the click-chemistry compatible functional group(e.g. terminal alkyne or terminal azide group).

With continuing reference to FIG. 6, method 600 includes operation 604,where the precursor formed in operation 602 is reacted with a compoundcomprising a photo polymerizable group in order to form a protectedreactive diluent.

Further still, in operation 606 of method 600 the protected reactivediluent is mixed with a photo polymerizable compound, e.g. a crosslinkeras shown in FIG. 3, to form an additive manufacturing resin. The mixturemay be created using any suitable technique, and may include one or moresuch crosslinkers, preferably the crosslinkers have a suitably lowviscosity to allow rapid additive manufacturing in a layer-wise fashion.

In various embodiments, method 600 may include any number of additionalor alternative features, operations, may be performed under specifiedconditions, etc. as would be appreciated by a person having ordinaryskill in the art upon reading the present disclosure.

For instance, in one embodiment the photo polymerizable compound may beor include a polyethylene-glycol backbone functionalized with at leastone photo polymerizable moiety selected from a group consisting of:acrylates, epoxides, and thiol-enes. Additionally and/or alternatively,the photo polymerizable compound comprises a hexanediol backbonefunctionalized with at least one photo polymerizable moiety selectedfrom a group consisting of: acrylates, epoxides, and thiol-enes. Assuch, the photo polymerizable compound in various embodiments mayinclude PEGDA, EGDMA, PETA, HDDA, etc. In more embodiments, thephoto-polymerizable compounds described herein may include any moiety,structure, etc. as set forth in FIG. 16.

In more embodiments, the protecting reagent may include a protectinggroup selected from a group consisting of: a trimethylsilyl, atriethylsilyl, a t-butyl dimethylsilyl, a triisopropylsilyl, and a2-(2-hydroxypropyl)alkyne, e.g. as shown in FIG. 7A. As further shown inFIG. 7A, and according to various embodiments the protecting group maysubsequently be removed (i.e. the click-chemistry compatible group maybe deprotected) by exposing the protecting groups to conditions such asfluoride, silver nitrate, alkali conditions (e.g. refluxing sodiumhydroxide).

For instance, in preferred embodiments where the protecting group ispresent during formation of three-dimensional structures viaphoto-activated additive manufacturing, and even after suchmanufacturing the protecting group remains functionalized to theclick-chemistry compatible group. Accordingly, deprotection may involvesubmerging or washing the structure in a solution of one or more of theforegoing deprotecting agents, e.g. a dilute fluoride solution, silvernitrate solution, alkali solution, etc. as would be understood by aperson having ordinary skill in the art upon reading the presentdisclosures.

As shown in FIG. 7B, the materials generally disclosed herein assuitable for inclusion in additive manufacturing resins, andparticularly the protective dilutive reactants synthesized according toa reaction scheme 300 as shown in FIG. 3 may be characterized by astructure including a polymerizable group, e.g. an acrylate, epoxide,and/or thiol-ene, a linker (see e.g. FIG. 16), a click-chemistrycompatible group, e.g. a terminal alkyne or azide, and a protectinggroup functionalized on the click-chemistry compatible group. In orderto further functionalize the structures formed, e.g. by additivemanufacturing as alluded-to above, the protecting group may be removed,as further depicted in FIG. 7B. Thereafter, further functionalizationmay be carried out via a click chemistry reaction, such as a CuAACreaction 1200 as shown in FIG. 12. Of course, other click chemistryreactions and schemes disclosed herein may be employed without departingfrom the scope of the presently disclosed inventive concepts.

Again, it should be understood that although the click-chemistrycompatible functional groups depicted in FIGS. 7A and 7B are terminalalkynes, in various embodiments terminal azides may be substituted forthe terminal alkyne without departing from the scope of the inventiveconcepts discussed herein. Similarly, any equivalent click-chemistrycompatible functional group that would be appreciated by a skilledartisan upon reading the present disclosures may be employed, andequivalent protecting groups therefor, without departing from the scopeof the presently described inventive concepts.

In more embodiments of method 600, reacting the compound comprising theterminal alkyne group or a terminal azide group with the protectingreagent attaches a protecting group to the terminal alkyne group or theterminal azide group, and the reaction may be performed in the presenceof an organolithium reagent (e.g. n-butyllithium) and an acid (e.g. astrong acid such as hydrochloric acid).

Further still, according to various embodiments of method 600, reactingthe precursor with the compound comprising the photo polymerizable groupis performed in the presence of a base, such as DIPEA.

While the embodiments described above are characterized by compoundsincluding a terminal alkyne for the purpose of conveying click-chemistrycompatibility to the resulting resins and structures, it will beappreciated that the presently disclosed inventive concepts areinclusive of embodiments where the functional group(s) included toconvey click-chemistry compatibility include terminal azides, inaddition or alternatively to terminal alkynes.

For instance, a reaction scheme 400 as shown in FIG. 4 depicts asimplified synthetic pathway suitable for forming compounds havingterminal azides as well as functional groups suitable for crosslinkingto enable photo-activated additive manufacturing. As shown in FIG. 4,the reaction scheme 400 results in synthesis of a compound having anacrylate and a terminal azide. Of course, other functional groupssuitable for photo-activated additive manufacturing, such as epoxidegroups and/or thiol-ene groups (see e.g. FIGS. 14 and 15) may beincluded in any combination in compounds also having terminal alkynesand/or azides and thus provide both click-chemistry compatibility andphoto-activated additive manufacturing capability, in variousembodiments.

Returning now to FIG. 7A, in various embodiments protecting groups maybe functionalized to the click-chemistry compatible functional groups ofthe presently disclosed inventive compounds. For example, suitableprotecting groups may comprise or be a trialkylsilyl group, e.g.trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS),triisopropylsilyl (TIPS), and/or a 2-(2-hydroxypropyl) group.

Similarly, and as shown particularly in FIG. 7B, the protecting groupsmay be removed (i.e. deprotection may be accomplished) using suitablechemistry that would be appreciated by a skilled artisan reading thepresent disclosures and depending on the identity of the protectinggroup. For instance, where the protecting group comprises or is atrialkylsilyl group, e.g. trimethylsilyl (TMS), triethylsilyl (TES),t-butyldimethylsilyl (TBS), or triisopropylsilyl (TIPS), deprotectionmay include treatment with a fluoride, silver nitrate, and/or alkalisolution. Where the protecting group comprises or is not atrialkylsilyl, e.g. a 2-(2-hydroxypropyl) group, deprotection mayinclude refluxing the compound with a strong base such as sodiumhydroxide, potassium hydroxide, etc. Of course, other deprotectionchemistries may be employed without departing from the scope of thepresently disclosed inventive concepts, e.g. using equivalents to theabove schemes that would be appreciated by a person having ordinaryskill in the art upon reading the present descriptions.

With continuing reference to FIG. 7B, click-chemistry compatiblecomponents of additive manufacturing resins (especially those componentswhich comprise the dilutive reactant component of a dual-componentresin) may be structurally characterized by including a polymerizable(or crosslinking) group such as an acrylate, thiol-ene, epoxide, etc.and a click-chemistry compatible group such as a terminal alkyne or aterminal azide (optionally protected) joined by a linker chain. Variousembodiments of suitable linkers are shown in FIG. 16, and may generallyinclude aliphatic groups, polyethylene groups, aromatic groups,dimethylsiloxane groups, esters, amides, amines, ethers, ureas,carbamates, carbonates, and/or sulfones. These linkers may becharacterized by being R-substituted, where R may include methyl,hydrogen, alkyl and/or aryl moieties in various approaches.

Turning now to FIGS. 8A-8B, and as alluded to previously, the additivemanufacturing resins described above may be utilized in an additivemanufacturing process to form unique structures with precisely definedfeatures, e.g. on the scale of several hundred nanometers in preferredembodiments. As depicted in FIGS. 8A-8B, an octahedral truss has beenformed according to one embodiment using materials and techniques asdescribed herein. The same truss is shown in both FIGS. 8A and 8B, whilethe truss as depicted in FIG. 8B is exposed to ultraviolet light inorder to cause an organic additive (coumarin) functionalized thereto viaclick-chemistry to fluoresce. The structures shown in FIGS. 8A and 8Bwere created as a proof-of-principle demonstration of the ability toincorporate click-chemistry compatible groups into additivemanufacturing resins, create click-chemistry compatible structures viaadditive manufacturing using such resins, and functionalize theresulting structures via click-chemistry.

Accordingly, in various embodiments a composition of matter consistentwith the inventive concepts disclosed herein includes athree-dimensional structure comprising photo polymerized and/orcrosslinked molecules, where surfaces of the three-dimensional structureare functionalized with one or more click-chemistry compatiblefunctional groups. In various embodiments, and depending on the natureof the additive manufacturing resin utilized to form thethree-dimensional structure, the click-chemistry compatible functionalgroups may optionally but preferably be protected with a protectinggroup or reagent. The protecting group or reagent may be removed (i.e.the structure may be deprotected) using appropriate chemistry asdescribed in further detail below to allow click-chemistry basedfunctionalization of the structure, or at least surfaces thereof.

The click-chemistry compatible functional groups are preferablyconfigured to engage in a click-chemistry reaction as disclosed herein,particularly preferably a copper-catalyzed azide-alkyne cycloaddition(CuAAC) reaction, e.g. via inclusion of terminal alkynes, azides, orboth. Thus, in more embodiments, at least some of the click-chemistrycompatible functional groups are structurally characterized byconversion into triazoles via the CuAAC reaction, as discussed infurther detail below regarding FIG. 9.

More preferably, at least some of the click-chemistry compatiblefunctional groups are protected by one or more protecting groups, suchas a functional group selected from a group consisting of: atrimethylsilyl, a triethylsilyl, a t-butyl dimethylsilyl, atriisopropylsilyl, and a 2-(2-hydroxypropyl) group.

In one embodiment, photo polymerizable and/or crosslinking precursorcompounds preferably include functional groups that are selected fromacrylates, epoxies, thiol-enes, and/or other click-compatiblechemistries as set forth herein. One or more of the foregoing functionalgroups may be present in various implementations. Accordingly, the photopolymerized molecules of the composition of matter may preferablyinclude one or more photo polymerized moieties formed from polymerizingprecursor compounds having photo polymerizable group(s) selected from:acrylates, epoxies, and thiol-enes.

In one embodiment, at least some of the click-chemistry compatiblefunctional groups are functionalized with an additive selected from agroup consisting of an antibiotic and an antibacterial compound, such assilver ions and/or fimbrolides.

The composition of matter may optionally be functionalized such that atleast some of the click-chemistry compatible functional groups form aself-assembled monolayer (SAM), and the SAM may be or include aclick-chemistry compatible polymer such as an azide or alkyne terminatedpoly(polyethylene glycol)) methacrylate, and/or derivatives thereof.

Further still, at least some of the click-chemistry compatiblefunctional groups may be functionalized with silica dioxidenanoparticles in embodiments configured to provide tunable wettabilityto the structure.

The click-chemistry compatible functional groups may additionally oralternatively be functionalized to render the surfaces of thethree-dimensional structure hydrophobic, or hydrophilic, e.g. viafunctionalization with compounds having hydrophobic and/or hydrophilicmoieties. In various approaches certain surfaces of the structure may berendered hydrophobic, while other surfaces may be rendered hydrophilic.

Further still, some or all of the click-chemistry compatible functionalgroups may be functionalized with a pharmacophore.

The three-dimensional structure may be solid throughout a bulk thereof,or may be porous in certain portions or throughout the bulk.

The three-dimensional structure, particularly in embodiments whereformation thereof is achieved via projection microstereolithography, maybe characterized by features having a size in a range from severalhundred nanometers to several hundred microns. Of course, other featuresizes and ranges thereof as disclosed herein may be employed withoutdeparting from the scope of the presently disclosed inventive concepts.

A simplified process 900 for forming the structures shown in FIGS. 8A-8Bis shown according to one embodiment in FIG. 9. In particular, theprocess 900 involves forming (e.g. via additive manufacturing techniquessuch as projection microstereolithography) a three-dimensional structure904 from an additive manufacturing resin 902. As shown in FIG. 9, theresin 902 employed to form the octahedral truss shown in FIGS. 8A and 8Bis a dual-component resin (e.g. 306) and includes a photoactivator (e.g.irgacure 819), a protected click-chemistry compatible component and acrosslinker component (e.g. PEGDA 250). Although the formation processreferenced by FIG. 9 comprises photo activated additive manufacturing,any suitable formation process that would be appreciated by skilledartisans upon reading the present disclosure may be utilized withoutdeparting from the scope of the presently disclosed inventive concepts.

The formation process shown in FIG. 9 results in a three-dimensionalstructure 904 such as the octahedral truss shown in FIGS. 8A-8B, wheresurfaces of the structure 904 are characterized by functionalizationwith a click-chemistry compatible group, e.g. a terminal alkyne orazide, which is protected, e.g. with TMS. The entire surface area of thestructure 904 may be so functionalized, or selected portions thereof maybe functionalized, in various embodiments. The bulk of the structure 904may comprise crosslinked molecules formed from components of the resin902, and optionally other resin(s).

For instance, the formation process may include using different resinsat different points of time while forming the structure 904, some ofwhich may include a click-chemistry compatible component, and others ofwhich may omit such click-chemistry compatible components. In moreapproaches, a digital mask may define select portions of the resin 902to cure (e.g. via crosslinking) and some portions may correspond to aregion within the resin bath that include click-chemistry compatiblecomponents, while other regions may not include such click-chemistrycompatible components.

A fluidics system may facilitate such selective presence ofclick-chemistry compatible components in different regions of aprecursor bath (e.g. 116), e.g. by flowing different resin compositionsinto a chamber at different times throughout the formation process,and/or by creating standing channels in different regions of thechamber.

After forming the structure, the click-chemistry compatible groups maybe deprotected to form a deprotected click-chemistry compatiblestructure 906. Deprotection may be accomplished by washing surfaces ofthe structure 904 with a solution of deprotecting agent (e.g. asdiscussed above). As depicted in FIG. 9, the deprotecting agentcomprises a solution of dilute tetra-n-butylammonium fluoride in aceticacid. The resulting deprotected click-chemistry compatible structure 906is thus ready for functionalization with a suitable organic additive viaa click-chemistry reaction. Organic additives may include any moleculeincluding a click-chemistry compatible functional group (e.g. alkyne,azide, and/or preferably a terminal alkyne or azide). This flexibilityprovides very broad applicability of the presently disclosed inventiveconcepts in terms of functionalizing custom-designed three-dimensionalstructures for a variety of purposes, as discussed further below.

Referring again to FIG. 9 and process 900, the deprotectedclick-chemistry compatible structure 906 may be functionalized withcoumarin 908 (compound E) by placing the coumarin 908 in proximity tothe deprotected click-chemistry compatible structure 906 in the presenceof a catalyst. In various embodiments, the catalyst may include one ormore catalysts selected from a group consisting of copper (I),ruthenium, silver, gold, iridium, nickel, zinc, and lanthanum.

This results in a CuAAC reaction (see process 1200 of FIG. 12) wherebythe terminal alkyne of the deprotected click-chemistry compatiblestructure 906 reacts with the azide group of the coumarin 908 to causecycloaddition of coumarin 908 to the structure 906, resulting in afunctionalized structure 910. FIGS. 8A and 8B demonstrate this structurewas the result of the CuAAC reaction, since coumarin 908 is notfluorescent under UV light, but the resulting structure 910 exhibitedfluorescence (via the triazole groups) as expected.

In various embodiments, the terminal alkyne and azide may be present onthe structure 906, the organic additive (e.g. coumarin 908)interchangeably. Other click-chemistries and suitable functional groupstherefor that would be understood as equivalent to those shown in FIG. 9may be employed without departing from the scope of the presentlydescribed inventive concepts.

Accordingly, and with reference to FIG. 10, in various embodiments amethod 1000 of forming a click-chemistry compatible structure includes,in operation 1002, exposing, e.g. according to a three-dimensionalpattern such as described above regarding FIG. 1, select portions of anadditive manufacturing resin to a wavelength of light configured tocause a photo polymerizable compound such as a crosslinking agent in theadditive manufacturing resin to polymerize (e.g. crosslink), therebyrendering the exposed portions of the additive manufacturing resin intoa solid layer of the click-chemistry compatible structure. Preferably,the additive manufacturing resin comprises at least one compound havinga click-chemistry compatible functional group and more preferably thephoto polymerizable compound includes click-chemistry compatiblefunctional group(s).

The method 1000 may optionally include any combination of additionaloperations, features, etc. as disclosed herein without departing fromthe scope of the present disclosure. In one approach, the portions ofthe additive manufacturing resin exposed to the wavelength of light aredefined according to a predetermined mask.

The method 1000 in other approaches may include submerging the solidlayer of the click-chemistry compatible structure in the additivemanufacturing resin; and exposing either the portions of the additivemanufacturing resin or other portions of the additive manufacturingresin to the wavelength of light to form a second layer of theclick-chemistry compatible structure. Again, the exposure may beperformed according to a predefined, preferably three-dimensional,pattern.

The method 1000 in still other approaches may include iterativelyrepeating the submerging and the exposing to form a plurality of layersof the click-chemistry compatible structure according to a predeterminedthree-dimensional pattern.

The wavelength of light may be selected based on an excitationwavelength of a photoinitiator in the resin, and in some approaches(such as shown in FIG. 9) may be a wavelength in the ultraviolet (UV)range. In various embodiments, the method 1000 may cause molecules topolymerize and/or crosslink according to reactive schemes 1300, 1400,and/or 1500 as shown respectively in FIGS. 13-15. The polymerizationand/or crosslinking preferably causes the exposed portions of aresin/precursor bath to precipitate into a layer of solid, optionallyporous material (e.g. where the resin includes pore-forming materials asdescribed herein, such as salts, uncrosslinked polystyrene beads, silicananoparticles, etc.).

Referring now to FIG. 11, a method 1100 of functionalizing aclick-chemistry compatible structure may proceed according to operation1102, in which a click-chemistry compatible structure is reacted with anorganic additive. The click-chemistry compatible structure reacted withthe organic additive includes a plurality of click-chemistry compatiblemolecules each independently having one or more click-chemistrycompatible functional groups (e.g. terminal alkynes and/or azides, inone embodiment). The click-chemistry compatible molecules arefunctionalized on surfaces of the structure; while the organic additiveincludes at least some compound(s) each independently having one or moreclick-chemistry compatible functional groups other than theclick-chemistry compatible functional groups of the moleculesfunctionalized on the surfaces of the structure (e.g. the other of theterminal alkyne or azide). Furthermore, the click-chemistry compatiblemolecules functionalized on the surfaces of the click-chemistrycompatible structure are structurally configured to react with the oneor more click-chemistry compatible functional groups of the organicadditive and thereby attach the organic additive to the click-chemistrycompatible structure via the click-chemistry compatible moleculesfunctionalized on the surfaces of the structure.

In one embodiment, for instance, the functional groups functionalized onthe surfaces of the click-chemistry compatible structure comprise onecomponent of a click-chemistry compatible reaction (e.g. terminal alkyneor terminal azide for a CuAAC reaction) while the functional groups ofthe organic additive comprise the other component of the click-chemistrycompatible reaction (e.g. the other of the terminal alkyne or terminalazide). In some embodiments, functional groups forming both componentsof the click-chemistry compatible reaction may be included in moleculesfunctionalized to the surfaces of the structure as well as included inthe organic additive. Of course, when click chemistry proceeds accordingto other schemes mentioned herein or as would be understood by a personhaving ordinary skill in the art upon reading the present disclosures,the respective functional groups may include corresponding components ofsuch other schemes so as to enable click-chemistry functionalization ofthe structure with moieties present in the organic additive oradditives.

The method 1100 may include any number or combination of alternativeand/or additional operations, features, etc. shown in FIG. 11, invarious embodiments. For instance, and according to preferable CuAACreactions, the functionalization reaction may optionally be performed inthe presence of a catalyst such as copper (I). As will be appreciated byskilled artisans upon reading the present disclosure, differentfunctionalizations may be carried out for different portions of thestructure, e.g. by selectively applying different organic additivesand/or catalysts to different portions of the structure, by usingdifferent types of click-chemistry on different portions of thestructure, etc. in various embodiments. Accordingly, the catalyst mayinclude one or more materials selected from a group consisting of copper(I), ruthenium, silver, gold, iridium, nickel, zinc, and lanthanum. Insome click chemistries, catalysts may be unnecessary to accomplish theclick reaction.

Even more preferably, the click-chemistry compatible structure comprisesa compound selected from a group consisting of: acrylates, epoxides andthiol-enes, which advantageously allows for projectionmicrostereolithography to be utilized to form the structure, asdiscussed above. Of course, formation techniques and procedures otherthan projection microstereolithography may be implemented, particularlyphoto polymerization-based techniques and procedures, without departingfrom the scope of the presently disclosed inventive concepts.

To confer useful added functionality to the functionalized structure,the organic additive in various embodiments may be or include anantibiotic and/or an antibacterial compound, such as silver ions and/orfimbrolides.

The method 1100 may additionally and/or alternatively includefunctionalizing at least some of the functional groups functionalized onthe surfaces of the click-chemistry compatible structure to form aself-assembled monolayer (SAM). The SAM may be or include a compoundsuch as an azide- or alkyne-terminated poly(polyethylene glycol))methacrylate derivative, e.g. poly(polyethyleneglycol) methyl ethermethacrylate.

In more embodiments, and to convey improved wettability of thestructure's surfaces, the organic additive may include or be tethered tosilica dioxide nanoparticles.

The click-chemistry reaction may optionally include functionalizing atleast some of the functional groups on the surfaces of theclick-chemistry compatible structure, e.g. in order to render thesurfaces of the click-chemistry compatible structure hydrophobic, inother embodiments. Additionally and/or alternatively, the method 1100may include functionalizing at least some of the functional groupsfunctionalized on the surfaces of the click-chemistry compatiblestructure to render the surfaces of the click-chemistry compatiblestructure hydrophilic.

Further still, the organic additive may be or comprise a pharmacophoreto convey pharmacological utility to certain embodiments.

Applications/Uses

According to various embodiments, organic additives may be reacted withthe functionalized structures to convey anti-corrosive, anti-microbial,anti-fouling, tunable wettability, and/or pharmacophore deliverycharacteristics to the structures.

Regarding anti-corrosive surface modification, in one exemplary approachtriazoles, one product of copper-catalyzed azide-alkyne cycloaddition(CuAAC), are nitrogen-containing heterocyclic compounds that exhibitdesirable corrosion inhibition for metals and alloys against acid andalkaline media. As such, triazoles and related compounds are industrialimportant materials for coating purposes and may be formed on surfacesof the functionalized structure to provide anti-corrosivecharacteristics thereto.

In other approaches, antimicrobial agents can range from knownantibiotics to silver ions and can be used to prepare hygienic surfaces.Many antibiotics, for instance, are organic compounds that are thusamenable to manipulation through click chemistry such as CuAACreactions.

Similar to antimicrobial functionalization, in some embodiments clickchemistry such as CuAAC reactions can be employed to yieldself-assembling monolayers (SAM) coatings that may inhibit the adhesionsof proteins and/or other biological organisms. For instance, in oneexample hydrophilic an alkyne- or azide-terminated poly (polyethyleneglycol) methacrylate polymer, and/or derivative(s) thereof, may beutilized in a CuAAC reaction to form a SAM on surfaces of thefunctionalized structures disclosed herein, and such coatings mayprevent or significantly reduced the absorption of proteins such asbovine serum albumin (BSA).

Regarding wettability control, the capability/tendency for liquid(s) tomaintain contact with a solid surface may be selectivelycontrolled/tuned via click chemistry. For example, additivelymanufactured parts may be functionalized to exhibit either hydrophobicor hydrophilic surfaces, e.g. through surface chemistry modification. Inone embodiment, the structures discussed herein may have silica dioxidenanoparticles attached thereto using CuAAC, thereby improvingwettability of the material functionalized surfaces.

Turning now to pharmacophores, CuAAC can be employed as a means toquickly and reliable append a pharmacologically relevant molecule to thesurface of a material. More advanced systems may optionally feature abiodegradable and/or bio-activated linkage between the pharmacophore andthe CuAAC reactive groups, allowing the pharmacophore to be selectivelyreleased. For instance, an additively manufactured stint may be coatedwith an antibiotic, anti-cancer drug, and/or anti-cholesterol drug, suchthat the drug is slowly released over time when the stint is implantedin the patient. In another example, an additively manufactured producedporous substrate may be formed and configured to allow for biomedicalapplications, such as bone growth, in which the surface could bemodified through CuAAC, e.g. to enhance cell adhesion.

Various illustrative and exemplary embodiments of suitable surfacemodifications in different applications or fields of use have been setforth above by way of example. It should be understood that embodimentsof structures as described herein may include one or more of theforegoing exemplary functionalization/modifications, as well as otherfunctionalization/modifications that would be appreciated by a personhaving ordinary skill in the art upon reading the instant disclosure,without departing from the scope of the inventive concepts set forthherein.

The inventive concepts disclosed herein have been presented by way ofexample to illustrate the myriad features thereof in a plurality ofillustrative scenarios, embodiments, and/or implementations. It shouldbe appreciated that the concepts generally disclosed are to beconsidered as modular, and may be implemented in any combination,permutation, or synthesis thereof. In addition, any modification,alteration, or equivalent of the presently disclosed features,functions, and concepts that would be appreciated by a person havingordinary skill in the art upon reading the instant descriptions shouldalso be considered within the scope of this disclosure.

While various embodiments have been described above, it should beunderstood that they have been presented by way of example only, and notlimitation. Thus, the breadth and scope of a preferred embodiment shouldnot be limited by any of the above-described exemplary embodiments, butshould be defined only in accordance with the following claims and theirequivalents.

What is claimed is:
 1. A composition of matter, comprising: a three-dimensional structure comprising pattern-wise photo polymerized molecules; wherein at least some of the photo polymerized molecules comprise one or more protected click-chemistry compatible functional groups; and wherein at least portions of one or more surfaces of the three-dimensional structure are functionalized with one or more of the protected click-chemistry compatible functional groups.
 2. The composition of matter as recited in claim 1, wherein the one or more protected click-chemistry compatible functional groups are selected from a group consisting of: an alkyne coupled to a protecting group and an azide coupled to the protecting group; and wherein the protecting group is selected from a group consisting of: a trimethylsilyl, a triethylsilyl, a t-butyl dimethylsilyl, a triisopropylsilyl, and a 2-(2-hydroxypropyl)alkyne.
 3. The composition of matter as recited in claim 1, wherein the three-dimensional structure is structurally characterized by features having a feature size on a scale of several hundred nanometers to several millimeters.
 4. The composition of matter as recited in claim 3, wherein the features are independently selected from the group consisting of: protrusions, depressions, voids, lattices, channels, pockets, pillars, points, overhangs, cantilevers, and positive features extending away from a surface of the three-dimensional structure.
 5. The composition of matter as recited in claim 1, wherein the three-dimensional structure is spatially arranged as an octahedral truss.
 6. The composition of matter as recited in claim 1, wherein the three-dimensional structure is porous throughout a bulk thereof.
 7. The composition of matter as recited in claim 1, wherein the three-dimensional structure is porous throughout one or more predetermined portions of a bulk thereof.
 8. The composition of matter as recited in claim 1, wherein at least some of the photo polymerized molecules comprise one or more deprotected click-chemistry compatible functional groups.
 9. The composition of matter as recited in claim 8, wherein at least portions of one or more surfaces of the three-dimensional structure are functionalized with one or more of the deprotected click-chemistry compatible functional groups.
 10. The composition of matter as recited in claim 1, wherein at least portions of one or more surfaces of the three-dimensional structure are functionalized with hydrophobic moieties via the click-chemistry compatible functional groups.
 11. The composition of matter as recited in claim 1, wherein at least portions of one or more surfaces of the three-dimensional structure are functionalized with hydrophilic moieties via the click-chemistry compatible functional groups.
 12. The composition of matter as recited in claim 1, wherein at least portions of one or more surfaces of the three-dimensional structure are functionalized with at least one pharmacophore via the click-chemistry compatible functional groups.
 13. The composition of matter as recited in claim 1, wherein at least portions of one or more surfaces of the three-dimensional structure are functionalized with silica dioxide nanoparticles via the click-chemistry compatible functional groups.
 14. The composition of matter as recited in claim 1, wherein at least portions of one or more surfaces of the three-dimensional structure are functionalized with at least one antibiotic via the click-chemistry compatible functional groups.
 15. The composition of matter as recited in claim 1, wherein at least portions of one or more surfaces of the three-dimensional structure are functionalized with at least one antibacterial compound via the click-chemistry compatible functional groups.
 16. The composition of matter as recited in claim 15, wherein the antibacterial compound comprises either or both of: silver ions, and fimbrolides.
 17. The composition of matter as recited in claim 1, wherein at least some of the click-chemistry compatible functional groups are present in the form of a self-assembled monolayer (SAM).
 18. The composition of matter as recited in claim 1, wherein the click-chemistry compatible functional groups are protected via a trialkylsilyl group or a 2-(2-hydroxypropyl) group attached thereto.
 19. The composition of matter as recited in claim 18, wherein the trialkylsilyl group is selected from the group consisting of: trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), and combinations thereof. 